The stimulus-secretion coupling of glucose-induced insulin release. XII. Effects of diazoxide and gliclazide upon 45 calcium efflux from perifused islets.
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Biomedical subjects
Publications and source records attributed to D G Pipeleers.
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Glyceraldehyde is known to stimulate insulin release. Its influence on various parameters of islet function was investigated in order to assess the possible significance of glycolsis in the insulinotropic action of glucose. In the absence of glucose, glyceraldehyde (5-20 mM), but neither dihydroxyacetone nor glycerol stimulated insulin release in rat isolated islets. The glucose-like effect glyceraldehyde (10 mM) was characterized by a shift to the left of the curve relating insulin release to glucose concentration, without any significant increase in the maximal velocity of the secretory process. In the isolated perfused rat pancreas, glyceraldehyde provoked a biphasic secretory response. Glyceraldehyde-induced insulin release was inhibited in the absence of calcium or in the presence of epinephrine, unaffected by mannoheptulose or 3,3-tetramethyleneglutaric acid, and enhanced by theophylline and cytochalism B. Glyceraldehyde also stimulated to pro-insulin biosynthesis and 45Ca net uptake by isolated islets, the latter effect being apparently due, in part at least, to inhibition of calcium outward transport across the cell membrane. At concentrations of nearly equivalent insulinotropic potency, glucose and glyceraldehyde were metabolized at rates yielding comparable output of both lactate and 14CO2. The data indicate that glyceraldehyde mimics many effects of glucose on islet function, suggesting that the insulinotropic action of glucose may be related to its metabolism through the glycolytic pathway.
Clinical islet transplantation requires graft preservation conditions with a minimal loss in viable beta cells. The present study examines whether rat pancreatic beta cells survive a 96 h storage period at 4 degrees C. In a single cell viability assay, less than 20% viable cells were counted after 48 h storage in physiological HAM's F10 medium; cell survival was better in the high potassium solutions UW or Collins and further improved by supplementing Collins with albumin and benzamidine (CAB-77% viability after 96 h). Suspended beta cell aggregates were also well preserved during 4 days in CAB-4 degrees C as judged from DNA recovery and electron microscopy. After cold-storage in CAB, beta cells exhibited a higher insulin content than after culture in HAM's F10 at 20 degrees or 37 degrees C, but their capacity for subsequent insulin synthesis and release was comparable. When isolated islets were stored in CAB-4 degrees C for 96 h, they yielded slightly higher numbers of dissociated cells than after culture in HAM's F10 at 20 degrees C. Implantation of cold stored islets from 2 donor pancreata corrected hyperglycemia in streptozotocin-diabetic rats. It is concluded that rat beta cells can be stored in a supplemented Collins solution for at least 4 days at 4 degrees C, with preservation of initial cell number, hormone content and glucose responsiveness. During short-term periods, this new storage condition is at least equivalent to cultures at 20 degrees or 37 degrees C. Further studies are needed to assess any advantage for long-term storage of islet cell grafts.
Diabetes registries have documented that the lifetime risk of diabetes amounts to at least 10% in the western world. Moreover the prevalence of type 2 diabetes is increasing worldwide especially in developing countries. Furthermore there is a secular trend toward earlier clinical manifestation of both type 1 and type 2 diabetes. In the absence of a permanent cure for primary diabetes the present estimated number of at least 150 million diabetic patients worldwide is expected to double within the next 20 years. Consequently a sharp increase in the global burden of chronic diabetes complications is to be feared in the coming decades. Therefore it is absolutely mandatory to intensify research efforts aiming at identifying the etiological factors involved and designing effective strategies for prediction and prevention of the disease and its devastating complications. Diabetes registries constitute instruments of choice to conduct such studies because they are able to collect standardised clinical, demographic and biological information from sufficiently large representative groups of patients and risk groups such as first degree relatives. Since 1989, the Belgian Diabetes Registry is studying all types of diabetes presenting before age 40 in Belgium and provides a paradigm of how diabetes registries may also contribute to the advancement of knowledge on disease heterogeneity, etiology, prediction and prevention.